INTRODUCTION — This section highlights selected specific new recommendations and/or updates that we anticipate may change usual clinical practice. Practice Changing UpDates focus on changes that may have significant and broad impact on practice, and therefore do not represent all updates that affect practice. These Practice Changing UpDates, reflecting important changes to UpToDate over the past year, are presented chronologically, and are discussed in greater detail in the identified topic reviews.
ONCOLOGY (June 2020)
Pembrolizumab versus first-line chemotherapy for mismatch repair-deficient metastatic colorectal cancer
Between 3 and 6 percent of metastatic colorectal cancers (mCRCs) are deficient in DNA mismatch repair (dMMR), for which potential benefit from immune checkpoint inhibitor immunotherapy has been shown after failure of initial systemic chemotherapy. Preliminary results from the KEYNOTE-177 trial suggest that front-line pembrolizumab offers better outcomes than first-line chemotherapy in this setting, with a doubling of progression-free survival, higher and more durable objective response rates, and fewer severe adverse effects . Overall survival data have not yet been presented. Based on these data, we now suggest first-line pembrolizumab monotherapy rather than systemic chemotherapy for patients with nonoperable dMMR mCRC. In June 2020, the US Food and Drug Administration (FDA) approved pembrolizumab for the first-line treatment of patients with unresectable or metastatic dMMR colorectal cancer. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'Initial therapy for DNA mismatch repair deficient/microsatellite unstable tumors' and "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'First-line immunotherapy'.)
INFECTIOUS DISEASES (May 2020)
Dexamethasone and remdesivir for COVID-19
●For hospitalized patients with severe COVID-19 who are receiving supplemental oxygen (including those who are on high-flow oxygen and noninvasive ventilation), we suggest remdesivir, if available, and low-dose dexamethasone (Grade 2C).
For hospitalized patients with severe COVID-19 who require mechanical ventilation or ECMO, we recommend low-dose dexamethasone (Grade 1B). We also suggest remdesivir, if available, for patients who have been intubated for a short period of time (eg, 24 to 48 hours) (Grade 2C).
If supplies of remdesivir are limited, we prioritize it for patients who are on low-flow oxygen only.
•In a randomized, open-label trial of >9000 patients hospitalized with COVID-19 in the United Kingdom, low-dose dexamethasone significantly reduced 28-day mortality among patients hospitalized with COVID-19 compared with usual care alone (21.6 versus 24.6 percent) . In subgroup analysis, the relative reduction in mortality appeared greater among patients on invasive mechanical ventilation than among those on noninvasive oxygen therapy. A mortality benefit was not seen among patients who did not require respiratory support.
•In a multinational trial of >1000 patients with confirmed COVID-19 and pulmonary involvement, remdesivir resulted in faster time to recovery (median 11 versus 15 days with placebo); a trend towards lower 14-day mortality was not statistically significant (7 versus 12 percent) . In subgroup analysis, there was a reduction in mortality with remdesivir among patients who required supplemental oxygen but were not on high-flow oxygen or greater support. In contrast, a randomized trial from China failed to show benefit, although confidence in these results was reduced by use of concomitant therapies, differences in baseline comorbidities between the groups, and failure to meet the target enrollment .
Uncertainties remain regarding optimal use of these agents. Nevertheless, for hospitalized patients with severe COVID-19, we use dexamethasone or remdesivir or both, depending on their oxygen or ventilatory requirements. (See "Coronavirus disease 2019 (COVID-19): Management in hospitalized adults", section on 'Severe (including critical) disease'.)
INFECTIOUS DISEASES (March 2020, Modified April 2020)
One-time HCV screening for all adults ≥18 years
●We suggest one-time screening for hepatitis C virus infection in all adults aged ≥18 years rather than selective screening (Grade 2C).
In April 2020, the US Centers for Disease Control and Prevention (CDC) recommended that all adults ≥18 years be screened at least once for chronic hepatitis C virus (HCV) infection . The CDC recommendations differ from the US Preventive Services Task Force (USPSTF) recommendations issued in March 2020, which included an upper age limit of 79 years for universal screening . Previously, screening was recommended only for patients who had certain risk factors or were born during certain decades, but this approach results in many missed diagnoses. The improved efficacy, tolerability, and accessibility of antiviral treatment for HCV also support a broader screening strategy. We agree with the new CDC recommendation for broad one-time screening in all adults, and we continue to suggest repeat screening in individuals with ongoing risk factors (algorithm 1). (See "Screening and diagnosis of chronic hepatitis C virus infection", section on 'Routine one-time screening for adults'.)
ONCOLOGY (March 2020)
Hippocampal avoidance whole brain radiation for treatment of brain metastases
●For most patients undergoing whole brain radiation therapy (WBRT) for treatment of brain metastases, we suggest use of hippocampal avoidance intensity-modulated radiotherapy rather than conventional WBRT (Grade 2C). Patients with metastases within 5 mm of the hippocampi should receive conventional WBRT.
For patients receiving whole brain radiation (WBRT) for brain metastases, neurocognitive decline is a feared complication that adversely impacts quality of life. Lowering the dose of radiation delivered to the hippocampi with intensity-modulated radiation therapy (IMRT) has been suggested as a way to improve neurocognitive outcomes compared with conventional WBRT. In a randomized, unblinded trial in over 500 patients with brain metastases, the use of hippocampal avoidance IMRT (HA-IMRT) led to a 26 percent relative reduction in the risk of cognitive toxicity compared with conventional WBRT . Patients in the HA-IMRT group reported less difficulty remembering things, less difficulty speaking, and greater improvement in fatigue at six months. Rates of brain control and overall survival were similar between groups, although confidence intervals were wide. All patients also received memantine, an N-methyl-D-aspartate antagonist that was shown to reduce the risk of neurotoxicity in a previous trial. Based on these results, we now suggest HA-IMRT rather than conventional WBRT in most patients who require WBRT for treatment of brain metastases, and we administer memantine concurrently. (See "Delayed complications of cranial irradiation", section on 'Prevention'.)
HEMATOLOGY (February 2020)
Less chemoimmunotherapy for limited stage diffuse large B cell non-Hodgkin lymphoma (DLBCL) with no adverse features
●For patients with limited stage (stage I or II) diffuse large B cell non-Hodgkin lymphoma (DLBCL) with no adverse features, we suggest four cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) rather than six or more cycles of R-CHOP, radiation therapy (RT) alone, or combined modality therapy (R-CHOP plus RT) (Grade 2C).
Limited stage (stage I or II) diffuse large B cell non-Hodgkin lymphoma (DLBCL) without adverse risk factors (ie, no bulky disease, normal lactate dehydrogenase [LDH], ECOG performance status 0-1) has an excellent prognosis when treated with the current standard approaches of either six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or three cycles of R-CHOP followed by radiation therapy (RT). To determine if less chemoimmunotherapy could achieve comparable outcomes with less toxicity, almost 600 patients ≤60 years with stage I-II DLBCL and no adverse risk factors were randomly assigned to four versus six cycles of R-CHOP . With median follow-up greater than five years, there was less hematologic and non-hematologic toxicity with four cycles of R-CHOP, while three-year progression-free survival (PFS) and estimated five-year PFS and overall survival were similar compared with six cycles. We now suggest four cycles of R-CHOP for treatment of adults of any age with limited stage DLBCL and no adverse features. (See "Initial treatment of limited stage diffuse large B cell lymphoma", section on 'No adverse features'.)
NEUROLOGY (December 2019)
Tranexamic acid for adults with acute traumatic brain injury
●For patients with moderate traumatic brain injury (Glasgow Coma Scale greater than 8 and less than 13) presenting within three hours of injury, we recommend immediate administration of tranexamic acid (Grade 1B).
Whether the antifibrolytic agent tranexamic acid benefits patients with acute traumatic brain injury (TBI) was previously uncertain. In the CRASH-3 trial, which included over 9000 adults presenting within three hours of TBI with a Glasgow Coma Scale (GCS) <13 or any evidence of intracranial bleeding on CT scan, those receiving tranexamic acid had a nonsignificantly lower rate of death related to head injury compared with placebo (18.5 versus 19.8 percent) . However, this difference was statistically significant when patients with unreactive pupils were excluded (11.5 versus 13.2 percent) and in the subgroup of patients with mild to moderate TBI (5.8 versus 7.5 percent). Adverse events were similar between groups, including the rate of vaso-occlusive events. Based on these results, we now recommend tranexamic acid in patients with moderate TBI presenting within three hours of injury. Tranexamic acid may also be reasonable in other patient groups, such as those with severe TBI and reactive pupils or those with mild TBI (GCS >12) and intracranial bleeding, but a benefit is less certain in these patients. (See "Management of acute moderate and severe traumatic brain injury", section on 'Antifibrinolytic therapy'.)
PEDIATRICS (November 2019)
Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis caused by the F508del variant
●For patients age ≥12 years old with cystic fibrosis who are homozygous for the F508del variant, we suggest a triple therapy regimen (elexacaftor-tezacaftor-ivacaftor) rather than dual therapy (tezacaftor-ivacaftor or lumacaftor-ivacaftor) (Grade 2B). For patients ≥12 years who have one F508del variant(heterozygotes), we suggest the triple therapy regimen rather than dual therapy or monotherapy with ivacaftor (Grade 2C).
Elexacaftor-tezacaftor-ivacaftor is a combination cystic fibrosis transmembrane regulator (CFTR) modulator designed to improve production and function of the defective CFTR protein in individuals with cystic fibrosis (CF) caused by the F508del CFTR variant. Two recent studies evaluated this combination drug in differing populations:
•In a randomized trial in >100 patients homozygous for the F508del variant, elexacaftor-tezacaftor-ivacaftor increased FEV1 at four weeks and improved respiratory symptoms compared with dual therapy (tezacaftor-ivacaftor) .
•In a separate placebo-controlled randomized trial in >400 patients age ≥12 years who were heterozygous for the F508del variant and had a second minimal function variant (ie, producing no CFTR protein or a protein unresponsive to ivacaftor or tezacaftor-ivacaftor), elexacaftor-tezacaftor-ivacaftor increased the FEV1 after four weeks of treatment, decreased pulmonary exacerbations by >60 percent, improved respiratory symptoms, and reduced sweat chloride .
The studies were the basis for approval by the US Food and Drug Administration of this combination drug for patients ≥12 years with the F508del variant (homozygotes or heterozygotes with 508del and any other disease-causing CFTR variant). We now recommend CFTR modulator therapy for most patients with CF and suggest triple therapy for patients with who are homozygous or heterozygous for the F508del CFTR variant, representing almost 90 percent of patients with cystic fibrosis in the United States. (See "Cystic fibrosis: Treatment with CFTR modulators", section on 'Efficacy'.)
HEMATOLOGY (November 2019)
Lenalidomide for high-risk smoldering multiple myeloma
Until recently, standard of care for patients with smoldering multiple myeloma (SMM) has been observation with systemic treatment deferred until progression to symptomatic disease. An earlier randomized trial demonstrated improved outcomes with lenalidomide plus dexamethasone (Rd), but concerns with the study design made extrapolation of the results difficult. In a second multicenter randomized trial of 182 patients with SMM, single-agent lenalidomide improved progression-free survival (PFS) and decreased end organ damage (eg, renal failure, bone lesions) when compared with observation . Serious (grade 3/4) adverse events occurred in 41 percent of patients in the treatment arm; there was one treatment-related death in the phase II run-in and none in the randomized phase. On subgroup analysis, the PFS benefit was definitive in those with high-risk SMM but less clear in those with intermediate-risk disease. For patients with high-risk SMM by the Mayo 2018 20/2/20 criteria, we now recommend treatment with single-agent lenalidomide or Rd rather than observation (algorithm 2). More intensive regimens, or treatment for lower-risk SMM, should be reserved for patients enrolled in clinical trials. (See "Smoldering multiple myeloma", section on 'Management of high-risk SMM'.)
CARDIOVASCULAR MEDICINE (October 2019)
Dapagliflozin for heart failure with reduced ejection fraction
●For patients with heart failure with reduced ejection fraction (HFrEF) who have persistent symptoms and an elevated serum natriuretic peptide level on optimal pharmacologic and device therapy, we recommend addition of dapagliflozin (versus no additional drug therapy) (Grade 1B).
Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce hospitalization for heart failure (HF) in patients with type 2 diabetes mellitus (DM), but whether they improve outcomes for nondiabetic patients with HF has not been known. The DAPA-HF trial evaluated the SGLT2 inhibitor dapagliflozin in nearly 5000 patients with symptomatic heart failure with reduced ejection fraction (HFrEF) and an elevated natriuretic peptide level on optimal drug and device therapy . Compared with placebo, all-cause mortality and the primary composite outcome (worsening HF or cardiovascular death) was reduced with dapagliflozin, with similar effects in patients with and without type 2 DM. The frequency of adverse effects was generally similar in the dapagliflozin and placebo groups. Given these findings, we now recommend dapagliflozin for patients with HFrEF with persistent symptoms and an elevated serum natriuretic peptide level despite optimal drug and device therapy (including a mineralocorticoid receptor antagonist and/or cardiac resynchronization therapy, if indicated). Dapagliflozin is contraindicated in patients with symptomatic hypotension or systolic blood pressure <95 mmHg, estimated glomerular filtration rate (eGFR) <30 mL per minute per 1.73 m2, or rapidly declining renal function. (See "Secondary pharmacologic therapy in heart failure with reduced ejection fraction (HFrEF) in adults", section on 'Evidence on dapagliflozin'.)
OBSTETRICS, GYNECOLOGY AND WOMEN'S HEALTH (August 2019)
New ACOG guidelines for preventing early-onset group B streptococcus infection in newborns
●Universal screening of pregnant women for Group B streptococcal (GBS) colonization is now recommended at 36 0/7 to 37 6/7 weeks of gestation, rather than the previously recommended 35 to 37 weeks. Women with GBS bacteriuria any time in pregnancy or who had an infant with early-onset GBS infection in a previous pregnancy can be excluded from culture-based screening as they should routinely receive intrapartum antibiotic prophylaxis.
The American College of Obstetricians and Gynecologists (ACOG) has released guidelines for prevention of early-onset group B streptococcus (GBS) infection in newborns, updating and replacing the obstetric portions of the 2010 guidelines from the Centers for Disease Control and Prevention (CDC) . Among the revisions, a GBS rectovaginal screening culture is now recommended at 36 0/7 to 37 6/7 weeks of gestation rather than at 35 to 37 weeks. Cultures obtained more than five weeks before delivery are not predictive of GBS status at the time of birth, and the later screening window decreases the number of women who need to be recultured if they have not delivered by their due date. In addition, in selected women with unknown GBS status and a history of GBS colonization in a previous pregnancy, clinicians may offer intrapartum prophylactic antibiotics as part of a shared decision-making process rather than basing the decision to initiate antibiotics on intrapartum risk factors or results of rapid testing. (See "Neonatal group B streptococcal disease: Prevention", section on 'Culture-based approach'.)